PROJECT SUMMARY/ABSTRACT Development of rehabilitation interventions that are both effective and appropriate for patients with severe upper limb paresis remains a major unmet clinical need. These patients have little to no volitional movement and therefore are left with a non-functional upper limb. Many rehabilitation therapies are inappropriate for this sub-population because they require significant residual movement. We have developed and tested a new therapy that can be delivered in patients with little to no residual hand/finger motion. Known as contralaterally controlled functional electrical stimulation (CCFES), the technique applies neuromuscular electrical stimulation (NMES) to paretic wrist, finger, and thumb extensors to produce hand opening. The patient controls the intensity of stimulation by wearing a glove with sensors on their unaffected contralateral hand. When the patient opens their unaffected hand, a proportional intensity of stimulation opens their paretic hand. Therefore, no residual movement of the paretic hand is necessary, which allows even patients with severe paresis to engage in functional task practice using the affected upper limb. We have shown in a recent RCT that CCFES is more effective than conventional NMES at reducing upper limb motor impairment in severe patients. But patients continue to experience limitation in functional abilities. The goal of this study is to build upon the gains achieved with CCFES in severe patients by augmenting its effects with another technique we have shown to facilitate improvements in this sub-population. Non-invasive brain stimulation delivered to facilitate the intact contralesional higher-motor cortices (cHMC) can have positive effects on upper limb motor control in severe patients. When extensive damage to ipsilesional corticospinal pathways renders the damaged ipsilesional primary motor cortex (iM1) ineffective at controlling paretic limb movement, intact, contralesional motor cortices especially the cHMC can contribute by changing the balance of interhemispheric inhibition between motor cortices and by increasing the excitability of uncrossed projections from the contralesional cortex to the paretic upper limb. Therefore, here, we will test the scientific premise that CCFES augmented with facilitation of cHMC will lead to greater upper limb motor improvement in severe patients than CCFES augmented with conventional facilitation of iM1 or than CCFES alone. Seventy-two patients with severe hand impairment will receive 12 weeks of CCFES + cHMC facilitation, CCFES + iM1 facilitation, or CCFES + sham brain stimulation. Assessments of upper limb motor function and neurophysiology will be completed at baseline, 6, 12, 24, and 36 weeks. This study will 1) determine whether cHMC facilitation augments the effects of CCFES to produce greater improvements in upper limb function in severe patients, 2) investigate the underlying neurophysiologic mechanisms contributing to restored paretic limb motor control, and 3) evaluate and identify patient factors that affect efficacy of CCFES + cHMC facilitation. !